- UREA DERIVATIVES AS CB1 ALLOSTERIC MODULATORS
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Heteroaryl and aliphatic analogs of diarylurea-based cannabinoid 1 receptor (CB1 R) allosteric modulators of formula (I) are described. Exemplary analogs can provide improved potencies and pharmacokinetic properties. Methods of using the analogs to treat
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Page/Page column 61; 62
(2021/01/23)
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- Synthesis and Pharmacological Evaluation of 1-Phenyl-3-Thiophenylurea Derivatives as Cannabinoid Type-1 Receptor Allosteric Modulators
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We previously reported diarylurea derivatives as cannabinoid type-1 receptor (CB1) allosteric modulators, which were effective in attenuating cocaine-seeking behavior. Herein, we extended the structure-activity relationships of PSNCBAM-1 (2) at the central phenyl ring directly connected to the urea moiety. Replacement with a thiophene ring led to 11 with improved or comparable potencies in calcium mobilization, [35S]GTPγS binding, and cAMP assays, whereas substitution with nonaromatic rings led to significant attenuation of the modulatory activity. These compounds had no inverse agonism in [35S]GTPγS binding, a characteristic that is often thought to contribute to adverse psychiatric effects. While 11 had good metabolic stability in rat liver microsomes, it showed modest solubility and blood-brain barrier permeability. Compound 11 showed an insignificant attenuation of cocaine seeking behavior in rats, most likely due to its limited CNS penetration, suggesting that pharmacokinetics and distribution play a role in translating the in vitro efficacy to in vivo behavior.
- Nguyen, Thuy,Gamage, Thomas F.,Decker, Ann M.,Barrus, Daniel,Langston, Tiffany L.,Li, Jun-Xu,Thomas, Brian F.,Zhang, Yanan
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p. 9806 - 9823
(2019/11/11)
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- Discovery of a potent, cell penetrant, and selective p300/CBP-associated factor (PCAF)/general control nonderepressible 5 (GCN5) bromodomain chemical probe
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P300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.
- Humphreys, Philip G.,Bamborough, Paul,Chung, Chun-Wa,Craggs, Peter D.,Gordon, Laurie,Grandi, Paola,Hayhow, Thomas G.,Hussain, Jameed,Jones, Katherine L.,Lindon, Matthew,Michon, Anne-Marie,Renaux, Jessica F.,Suckling, Colin J.,Tough, David F.,Prinjha, Rab K.
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supporting information
p. 695 - 709
(2017/02/05)
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- Pd-Catalyzed Suzuki coupling reactions of aryl halides containing basic nitrogen centers with arylboronic acids in water in the absence of added base
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The Pd-catalyzed Suzuki coupling reactions of a series of aryl chlorides and aryl bromides containing basic nitrogen centers with arylboronic acids in water in the absence of added base are reported. The reactions proceed either partially or entirely under acidic conditions. After surveying twenty-two phosphorus ligands, high yields of products were obtained with aryl chlorides only when a bulky ligand, 2-(di-tert-butyl-phosphino)-1-phenyl-1H-pyrrole (cataCXiumPtB) was used. In contrast, aryl bromides produced high yields of products in the absence of both added base and added ligand. In order to explore the Suzuki coupling process entirely under acidic conditions, a series of reactions were conducted in buffered acidic media using several model substrates. 4-Chlorobenzylamine, in the presence of cataCXiumPtB, produced high yields of product at buffered pH 6.0; the yields dropped off precipitously at buffered pH 5.0 and lower. The fall-off in yield was attributed to the decomposition of the Pd-ligand complex due to the protonation of the ligand in the more acidic aqueous media. In contrast, in the absence of an added ligand, 4-amino-2-chloropyridine produced quantitative yields at buffered pH 3.5 and 4.5 while 4-amino-2-bromopyridine produced quantitative yields in a series of buffered media ranging from pH 4.5 to 1.5. These substrates are only partially protonated in acidic media and can behave as active Pd ligands in the Suzuki catalytic cycle.
- Li, Zhao,Gelbaum, Carol,Campbell, Zachary S.,Gould, Paul C.,Fisk, Jason S.,Holden, Bruce,Jaganathan, Arvind,Whiteker, Gregory T.,Pollet, Pamela,Liotta, Charles L.
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supporting information
p. 15420 - 15432
(2017/12/15)
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- Α 7 as intranuclear hydroxynicotinic acetylcholine receptor quinuclidines compd.
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PROBLEM TO BE SOLVED: To provide ligands for the nicotinic α-7 receptor used for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.SOLUTION: The disclosure provides compounds of the specified formula I, including their salts, and compositions and methods using the compounds.
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Paragraph 0271; 0272
(2018/10/03)
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- QUINUCLIDINE COMPOUNDS AS ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS
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The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands for the nicotinic 7 receptor and may be useful for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.
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Page/Page column 136
(2011/05/11)
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- AZABIPHENYLAMINOBENZOIC ACID DERIVATIVES AS DHODH INHIBITORS
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New azabiphenylaminobenzoic acid derivatives having the chemcial structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of the dehydroorotate dihydrogenase (DHODH)
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- QUINUCLIDINE COMPOUNDS AS ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS
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The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands for the nicotinic α7 receptor and may be useful for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.
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Page/Page column 84
(2009/10/31)
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